Preparation for the relief of disease

ABSTRACT

A composition including (a) a Platelet Activating Factor (PAF) Inhibitor and (b) an antioxidant which interferes with the arachidonic acid cascade and also has antioxidant activity. The composition is useful for the treatment or the relief of inflammatory diseases, thrombosis, cardiac problems, and/or conditions caused by platelet induced blood clotting.

The present invention relates to preparations for the treatment orrelief of diseases, especially inflammatory diseases, in humans andanimals. In particular it relates to preparations for the treatment ofinflammatory respiratory diseases such as asthma in humans, especiallyin children.

Asthma is a chronic disease of the airways characterized by recurrentairway obstruction. Known treatments of asthma include daily doses ofpharmaceuticals such as inhaled corticosteroids, antihistamines andinhaled beta agonist bronchodilators such as Ventolin (RTM). The aim ofsuch treatments is to manage or ameliorate the condition, that is toprovide symptomatic relief of wheezing and/or breathlessness and/orcoughing. Unfortunately, even with such treatments, asthma sufferers areprone to severe asthma attacks or crises which may be brought on orexacerbated by other illness such as colds or influenza, allergens (forexample pollen, house dust etc.) or by exercise. Such crisis points mayinvolve unremitting coughing and other respiratory distress, and maynecessitate hospitalization and/or out-patient emergency care toadminister repeated bronchodilation therapy, oxygen therapy, and highdoses of oral glucocorticosteroids.

A major goal of asthma therapy is the prevention of crises which requireemergency therapy and/or oral corticosteroid treatment. This is for twomajor reasons. First, it is the crises which are the major cause of themorbidity and mortality associated with asthma. Secondly, recurrentsteroid use, especially at high doses of oral steroids, is associatedwith multiple adverse affects, which are well documented.

Inhalation therapy of asthma using an inhaler is the standard treatmentfor attacks other than severe acute attacks but has severaldisadvantages. It requires coordination of discharge of the inhaler withinhalation, which many people, especially children, find difficult. Italso requires considerable respiratory effort which those suffering fromasthma find difficult.

Beta 2 bronchodilators, e.g. salbutamol (Ventolin) and terbutaline(Bricanyl) are usually taken by inhalation but may be taken orally. Whentaken orally, these compounds have considerable adverse effects, such asinducing tremor and/or cardiovascular side effects (such adverse effectscan also follow inhalation administration but are less likely). The sideeffects are particularly bad at high doses. Oral steroids, e.g.,prednisolone and prednisone, which are used in acute asthma attacks,also have known (and considerable) side effects; these compounds aregenerally taken for a short period in order to alleviate the attackwhile avoiding those side effects.

Thus, known oral treatments for asthma either suffer from the severe andwell known side effects associated with glucocorticosteroids, or havenot proved very effective. There is, therefore, a considerable need foran effective oral treatment for asthma and other respiratory diseases.

According to the present invention, there is provided a compositionincluding (a) a Platelet Activating Factor (PAF) Inhibitor and (b) anantioxidant which interferes with the arachidonic acid cascade.Preferably, the antioxidant (b) is an NADPH oxide inhibitor. Preferably,the antioxidant (b) increases glutathione synthesis. Antioxidant (b) ispreferably a neutrophil oxidative burst antagonist.

Platelet-activating factor (PAF) is an ether-linked phospholipid (acetylglycerol ether phosphocholine) produced by many different kinds ofstimulated cells (e.g., basophils, neutrophils, monocytes, macrophages,endothelial cells) from phospholipids which are mobilized from cellmembranes by phospholipase A2. It is 100-to-10,000 times more potentthan histamine with respect to its vasoactive properties. As one of itssmooth muscle effects, it is a strong bronchoconstrictor. It alsostimulates other cells to increase their functional and metabolicactivities, i.e., primes or activates them for more effective function.It is a potent platelet-aggregating agent and inducer of systemicanaphylactic symptoms.

PAF inhibitor should be taken to mean an agent which inhibits PAF by anymechanism.

Preferably the Platelet Activating Factor (PAF) Inhibitor (a) is aginkgolide. Preferably the source of ginkgolide(s) is ginkgo biloba, orextract or component thereof.

Ginkgolides, for example, ginkgolide B, display potent (PAF) inhibitingactivity. This may lead to reduction of bronchoconstriction, inductionof airways hyperactivity and eosinophil response.

The structure of ginkgolide B (Molecular Formula: C₂₀H₂₄O₁₀) is shownbelow.

The ginkgolides are bioactive terpenes isolated from the roots, barkand/or leaves of Ginkgo biloba L., Ginkgoaceae. Other suitableginkgolides are those compounds which can be extracted from, forexample, the roots, bark and/or leaves of Ginkgo biloba L., Ginkgoaceaeby a polar organic solvent.

Arachidonic acid (AA) is the substrate from which eicosanoids, e.g.,prostaglandins, leukotrienes, and numerous other mediators, areproduced. Eicosanoids can collectively mediate almost every aspect ofthe inflammatory response. AA is produced from membrane phospholipidsand fatty acids through the effects of various phospholipases. AA is notstored in cells, however, it is produced and metabolized into mediatorsvery rapidly. The process by which eicosanoids is made (from AA) istermed the arachidonic acid AA cascade, and is well known. The mainmediating enzymes in the AA cascade are of the cyclooxygenase class,enzymes principally inhibited by aspirin and other NSAIDS, as well asCOX-2 inhibitors.

By “an antioxidant which interferes with arachidonic acid cascade” it ismeant any antioxidant that affects any stage of the AA cascade (forexample by inhibition of a mediating enzyme). The antioxidant may besaid to have two modes of action: (i) an antioxidant action; and (ii) anaction which affects the AA cascade.

Preferably, the antioxidant (b) is apocynin. This may be in isolatedform (e.g. apocynin), a precursor, for example the dimmer, the Glucoside(for example androsin), glycone or in the form of acetovanillone),and/or apocynin in natural form (e.g., in the form of picrorrhizakurroa). These forms are discussed in more detail below.

The compositions, preparations and methods according to the inventionare useful as (or in the manufacture of) pharmaceutical preparations forthe treatment of human patients, and/or as (or in the manufacture of)veterinary preparations for the treatment of non-human animals becausethey demonstrate activity as discussed below and shown in test data(see, for example, Example 13). The tests indicate that thecomposition(s) and/or preparation(s) are suitable for use in thetreatment or amelioration or relief of inflammatory disease. Preferably,they are used for the treatment or amelioration or relief ofinflammatory respiratory disease. “Inflammatory respiratory disease”includes respiratory diseases such as asthma, allergic airways diseaseand emphysema (e.g., hereditary emphysema), symptoms of allergymanifested in the respiratory system, exercise induced asthma andChronic Obstructive Pulmonary Disease (COPD) (bronchitis). Thepreparation may also be used to treat inflammatory diseases such asinflammatory joint disease, arthritis and rheumatoid osteoarthritis,(atopic) dermatitis, leishmaniasis and/or inflammatory diseases of thegastrointestinal tract, such as ulcers (including stomach ulcers,gastric ulcer syndrome, ulcerative colitis, coeliac disease, IrritableBowel syndrome, Irritable Bowel Disease and Crohn's disease. Thepreparations may also be used to prevent Platelet Induced bloodclotting, and thus are suitable for use in the treatment, managementand/or prevention of conditions caused by Platelet Induced bloodclotting (for example, Coronary Artery Disease, Arterial Clotting, PAD(peripheral arterial disease and Stroke). The preparations andcompositions may also be used in the treatment, management and/orprevention of thrombosis and cardiac related problems (for exampleischemia and blood flow problems, arrhythmias induced by experimentalmyocardial ischemia, prevention or reduction of arteriolar spasms andproblems caused by thrombus formation).

The compositions and preparations may be used to treat, manage, orprevent hayfever (allergic rhinitis). Preferred compositions for thisuse further comprise dimethyl sulfone.

The compositions may be used as (or in the manufacture of) veterinarypreparations for the treatment of non-human animals, for example, dogs,pigs, equine species, poultry and reared game birds such as pheasants.They may be used to treat inflammatory diseases such as seasonalpruritic determatitis, laminitis, eczematous dermatitis, COPD, lameness,azoturia, dermatitis, rain scald, osteoarthritis, hip dysplasia andleishamaniasis, equine gastroulcer syndrome, or the sequellae thereof.,

The combination of pharmaceutically significant amounts of activeingredients, antioxidant (b) (e.g., apocynin) and PAF Inhibitor (e.g.ginkgo biloba), may have a synergistic effect that leads to extremelyefficacious treatment of diseases, for example, asthma. Treatment usingpreparations of the invention may lead to considerable benefits ingeneral health, such as up to a 95% reduction in symptoms of asthma andother more general manifestations, such as increased wellness andhappiness, color (indicative of improved oxygenation), and, in children,apparent increased growth and development. There may also be asignificant reduction in the amount of crises and thus a decreased needfor hospital or out-patient treatment.

“Treatment using preparations of the invention” should be taken to meanboth administration of the preparation as a preventative or maintenancedose with the aim of prophylaxis (that is preventing or at leastreducing the frequency of attacks and therefore maintaining a level ofhealth, and/or preventing the development of a condition), and treatmentat a (generally higher) “therapeutic level” to alleviate chronic attacksor crisis symptoms which, if untreated, may lead to hospitalization.Thus, the preparation may remove or reduce the need for treatmentsconsidered harmful such as corticosteroids, especially oralcorticosteroid treatments. However, the preparations/compositions may beadministered in combination with conventional asthma treatments(Ventolin, oxygen therapy, corticosteroids, breathing techniques, etc.)without ill effects, and may enable the dose of conventional treatmentto be reduced (dose sparing).

Examples of compositions suitable for use as an antioxidant (b) areNADPH-oxidase inhibitors such as catechols and their metabolites andmethylated catechols, for example, apocynin.

Preferably, the antioxidant (b) is apocynin which is the plant-phenol4-hydroxy-3-methoxyacetophenone, and has the following formula:

Apocynin interferes with the arachidonic acid cascade, increasesglutathione synthesis, and is a neutrophil oxidative burst antagonist.These effects may contribute to the increased therapeutic effects shownby preparations including apocynin.

The antioxidant (b) may also be an apocynin derivative or a phenonederivative. Some examples of suitable phenone derivatives are disclosedin U.S. Pat. No. 5,481,043.

NADPH-oxidase inhibitors (suitable for use as antioxidant (b)) may befound in plant substances and plant extracts. For example, apocynin isfound in extracts of the plants picrorrhiza kurroa, apocynumcannabinium, apocynum venatum or apocynum androsaemifolium. Thepreparations of the invention may include an “isolated” NADPH-oxidaseinhibitor (for example “isolated” apocynin). Isolated NADPH-oxidaseinhibitor is an NADPH-oxidase inhibitor which has been synthesized, orNADPH-oxidase inhibitor which has been extracted from plants andpurified. Apocynin (or other NADPH-oxidase inhibitors) may be present inpreparations according to the invention as direct extracts from plants(i.e., as part of an unresolved mixture of compounds in the form of anunpurified plant or root extract). These will be referred to asNADPH-oxidase inhibitors (or apocynin) “in the natural form”. Forexample, apocynin present in preparations according to the invention inthe form of picrorrhiza kurroa will be referred to as “naturalapocynin”. Natural apocynin may include androsin and other iridoidglucosides, for example.

Preferably the composition includes antioxidant (b) which is anNADPH-oxidase inhibitor in a purified or synthetic form: “isolated”NADPH-oxidase inhibitor.

It is a still further preference that the antioxidant (b) which is anNADPH-oxidase inhibitor is present in both isolated form and a naturalform.

As discussed above, the preferred antioxidant (b) is apocynin. Ifapocynin is used in the preparation in “isolated form”, it is a furtherpreference that the preparation also comprises a natural form ofapocynin, for example, from an apocynin containing plant such aspicrorrhiza kurroa, apocynum cannabinium, apocynum venatum or apocynumandrosaemifolium, most preferably an extract from picrorrhiza kurroa.The use of the active entity in the natural form in combination with the“isolated” active entity may lead to a further synergistic effectbetween the isolated form (e.g., purified or synthetic apocynin) and thenatural form (e.g., apocynin contained in picrorrhiza kurroa). Thepreferred picrorrhiza kurroa is a standardized form based onstandardized iridoid glucoside fractions such as are well known. Apreferred picrorrhiza kurroa in standardized form comprises standardizediridoid glucoside fractions collectively known as “Kutkin min 4%”.Standardized iridoid glucoside fractions between Kutkin min 2% andKutkin min 8% are also preferred. In the Examples below, the picrorrhizakurroa in standardized form comprises standardized iridoid glucosidefractions collectively known as “Kutkin min 2%”.

The composition may include antioxidant (b) which is an NADPH-oxidaseinhibitor in natural form only, for example, picrorrhiza kurroa.However, if this is the case, it may be necessary to limit the amountsof picrorrhiza kurroa to prevent side effects (such as upset stomachwhich may occur due to other species in the picrorrhiza kurroa).However, it is noted that most human subjects can take up to 2,000 mg ofpicrorrhiza kurroa (Kutkin min 2%) per day without discomfort.

A preferred composition comprises:

a) ginkgo biloba; and

b) antioxidant, preferably NADPH-oxidase inhibitor, preferably apocynin;

wherein the ratio by weight of ginkgo biloba:antioxidant is betweenabout 3:10 and about 3.4:1, preferably between about 0.5:1 and about3:1, and more preferably between about 2.1:1 and 2.7:1.

In the ratio above, the weight of antioxidant refers to the weight inthe isolated form (e.g., apocynin in the isolated form).

Thus, according to the invention, in another aspect there is provided apharmaceutical preparation for the treatment or relief of inflammatorydisease, thrombosis, cardiac problems and/or conditions caused byPlatelet Induced blood clotting comprising (a) a Platelet ActivatingFactor (PAF) Inhibitor and (b) an antioxidant which interferes with thearachidonic acid cascade. Preferably, the antioxidant (b) is an NADPHoxide inhibitor. Preferably, the antioxidant (b) increases glutathionesynthesis. Antioxidant (b) is preferably a neutrophil oxidative burstantagonist.

Preferably the Platelet Activating Factor (PAF) Inhibitor is ginkgobiloba. Preferably the antioxidant (b) is apocynin.

The apocynin may be in isolated form. Preferably, the preparationfurther comprises apocynin in the natural form. Preferably thepreparation is a pharmaceutical preparation for the treatment ofinflammatory diseases in humans. Preferably, the preparation is for thetreatment of inflammatory respiratory diseases.

A preferred pharmaceutical preparation for inflammatory diseasecomprises:

a) ginkgo biloba; and

b) antioxidant, preferably NADPH-oxidase inhibitor, preferably apocynin;

wherein the ratio by weight of ginkgo biloba:antioxidant is betweenabout 3:10 and about 60:1, preferably between about 6:1 and about 0.4:1,more preferably between about 2.4:1 and about 0.45:1, even morepreferably between about 2.1:1 and about 1.4:1.

In the ratio above, the weight of antioxidant refers to the weight inthe isolated form (e.g., apocynin in the isolated form).

The preparations and compositions in the preceding paragraphs assume theginkgo biloba is in natural form. Preferably the ginkgo biloba is inconcentrated standard form, for example, a concentrated extract which isequivalent to four times the concentration of ginkgo biloba in thenatural form, such as Ginkgo biloba tablets sold by MediHerb ofAustralia (500 mg tablets containing ginkgo biloba concentrated extractequivalent to 2.0 g dry leaf ginkgo biloba standardized to Ginkgoflavone glycosides). Thus, a preferred preparation which includes ginkgobiloba in such a concentrated standard form comprises:

a) ginkgo biloba (in concentrated standard form);

b) an antioxidant, preferably NADPH-oxidase inhibitor, preferablyapocynin;

wherein the ratio by weight ginkgo biloba:antioxidant is between about30:1 and about 75:1000, preferably between about 3:1 and about 1:1, morepreferably about 3:2.

It is noted that in preparations according to the invention, a level ofantioxidant (b) (such as NADPH-oxidase inhibitor, for example, apocynin)higher than the minimum value specified above makes the preparation moresuitable for a therapeutic treatment, while an amount of antioxidant (b)of around the minimum value noted above makes the preparation moresuitable for a standard preventative measure treatment.

Preferably, the composition (or preparation) further comprises an agentwhich enhances lipid solubility of the preparation. This gives rise tobetween absorption and, hence, better bioavailability, especially by theoral route. Preferred agents which enhances lipid solubility are sourcesof pharmaceutically acceptable surfactants and/or fatty acids, forexample, phosphatidycholine (lecithin).

Preferably, the compositions or preparations further comprise dimethylsulfone. Such preparations are especially suitable for treating hayfever(allergic rhinitis).

The preparation may further comprise additional components such aspharmaceutically conventional carriers, diluents, flavourants,emulsifiers and stabilizers. Preferably the preparation furthercomprises one or more of the following:

i) an agent to enhance the immune system, for example, lactoferrin whichhas anti-viral, antibacterial and anti-oxidant effects;

ii) a natural source of vitamins or minerals such as bee pollen;

iii) a source, for example, a natural source, of vitamins, minerals andamino acids, for example, chlorella;

iv) a source of trace elements, for example, fucus vesiculosus; and/or

v) taste-masking agents, for example, yogurt, fruit juice, honey andsyrup.

The compositions and preparations are suitable for oral administration.Thus, in another aspect, the present invention provides an orallybioavailable preparation for the treatment or relief of inflammatorydisease, thrombosis, cardiac problems and/or conditions caused byPlatelet Induced blood clotting comprising (a) a Platelet ActivatingFactor (PAF) Inhibitor and (b) antioxidant which interferes with thearachidonic acid. Preferably, the antioxidant (b) is an NADPH oxideinhibitor. Preferably, the antioxidant (b) increases glutathionesynthesis. Antioxidant (b) is preferably a neutrophil oxidative burstantagonist.

Preferably, the Platelet Activating Factor (PAF) Inhibitor (a) is ginkgobiloba. Preferably, the antioxidant (b) is apocynin.

In a still further aspect, the present invention provides an orallybioavailable preparation for the treatment of inflammatory respiratorydisease comprising ginkgo biloba and apocynin. The apocynin may be inisolated form (e.g., apocynin as the dimmer, glycone or in the form ofacetovanillone) or in natural form (e.g., in the form of picrorrhizakurroa). Preferably, the apocynin is present in natural and isolatedforms.

Thus, the invention may provide an orally active anti-asthmaticpreparation. It will be appreciated that the preparations are suitablefor other means of administration, for example, mucosal delivery routes(for example, rectal, nasal, vaginal) and also topical administration.

According to the present invention, there is also provided a method oftreatment or relief of inflammatory disease, thrombosis, cardiacproblems and/or conditions caused by Platelet Induced blood clotting inhuman or other animal subjects comprising the step(s) of administeringto the subject (a) a Platelet Activating Factor (PAF) Inhibitor and (b)an antioxidant which interferes with the arachidonic acid cascade.

Preferably, the antioxidant (b) is an NADPH oxide inhibitor. Preferably,the antioxidant (b) increases glutathione synthesis. Antioxidant (b) ispreferably a neutrophil oxidative burst antagonist. The presentinvention also provides a method comprising use of (a) a PlateletActivating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade in the manufacture of amedicament for the treatment of inflammatory disease in humans or otheranimals.

Preferably, the method is for the treatment (and/or amelioration orrelief) of inflammatory respiratory diseases, for example, thosediscussed in the paragraphs above, for example, asthma, allergic airwaysdisease and emphysema (for example, hereditary emphysema), hayfever,allergic rhinitis, symptoms of allergy manifested in the respiratorysystem, exercise induced asthma and Chronic Obstructive PulmonaryDisease (COPD) (bronchitis). The method may also be used to treatinflammatory diseases such as inflammatory joint disease, arthritis andrheumatoid osteoarthritis, and/or inflammatory diseases of thegastrointestinal tract, such as ulcerative colitis, coeliac disease,Irritable Bowel syndrome, Irritable Bowel Disease and Crohn's disease.The method may be used to prevent platelet induced blood clotting,thrombosis, cardiac problems and other conditions discussed above.

Preferably, the Platelet Activating Factor (PAF) Inhibitor is ginkgobiloba. Preferably, the preparation is administered to a human at aconcentration, per daily dose, of ginkgo biloba (standardized to ginkgoflavone glycosides—24%) of 1 mg/kg body weight—25 mg/kg body weight.

Preferably, the antioxidant (b) is apocynin. Preferably, the preparationis administered to a human at a concentration, per daily dose, ofapocynin of 60 μg/kg body weight—20 mg/kg body weight.

Preferably, the method further comprises the step of administering anatural form of antioxidant (b), as described above, for examplepicrorrhiza kurroa. Preferably, the preparation is administered at aconcentration, per daily dose, of picrorrhiza kurroa of 1 mg/kg bodyweight—35 mg/kg body weight. This preferred daily dose of picrorrhizakurroa is based on standardized iridoid glucoside fractions collectivelyknown as “Kutkin min 4%”.

The above ranges are a maintenance dose (for prophylactic treatment) fora human patient. For a loading dose (e.g., to begin treatment or treatan acute attack) the daily dose should be doubled for a period of 1–5,preferably 3 days.

There may be a cumulative effect which provides clinical benefits over alonger period of 10 to 30 days.

The daily dose may be provided as a single capsule, tablet or othersolid or liquid form known to those skilled in the art, or may beprovided in divided doses (for example, 1 to 3 doses) to make up thefull daily dose. The doses of ginkgo biloba and antioxidant (b), forexample, apocynin, may be provided together in the capsule, tablet,etc., or the two may be provided as separate capsules or tablets (acapsule containing dose or partial dose of ginkgo biloba, and a separatecapsule containing the antioxidant (b), for example, apocynin) forsequential administration.

The following are preferred compositions/doses for the treatment ofanimals. The preferred Platelet Activating Factor (PAF) Inhibitor isginkgo biloba. Preferably, the antioxidant (b) is apocynin. Preferably,the method further comprises the step of administering a natural form ofantioxidant (b), as described above, for example, picrorrhiza kurroa.

For dogs, the preferred doses are a concentration, per daily dose, ofginkgo biloba (standardized to ginkgo flavone glycosides—24%) of 1 mg/kgbody weight—7 mg/kg body weight; a concentration, per daily dose, ofapocynin of 0.6 mg/kg body weight—35 mg/kg body weight. The dose mayalso comprise a daily dose of picrorrhiza kurroa of 3 mg/kg bodyweight—6.6 mg/kg body weight. The preferred daily dose of picrorrhizakurroa is based on standardized iridoid glucoside fractions collectivelyknown as “Kutkin min 4%”.

For horses, the preferred doses are a concentration, per daily dose, ofginkgo biloba (standardized to ginkgo flavone glycosides—24%) of 4 mg/kgbody weight—23 mg/kg body weight; a concentration, per daily dose, ofapocynin of 0.2 mg/kg body weight—1.1 mg/kg body weight. The dose mayalso comprise a daily dose of picrorrhiza kurroa of 1 mg/kg bodyweight—5.6 mg/kg body weight. The preferred daily dose of picrorrhizakurroa is based on standardized iridoid glucoside fractions collectivelyknown as “Kutkin min 4%”.

According to the present invention in a further aspect, there isprovided a kit of parts for a preparation for treatment or prevention ofinflammatory disease, thrombosis, cardiac problems and/or conditionscaused by Platelet Induced blood clotting in human or other animalsubject comprising at least one dose of (a) a Platelet Activating Factor(PAF) Inhibitor and (b) an antioxidant which interferes with thearachidonic acid cascade. Preferably the Platelet Activating Factor(PAF) Inhibitor is ginkgo biloba. Preferably the antioxidant (b) isapocynin.

It is envisaged that the kit of parts may be provided as, for example, ablister pack containing capsules containing doses or partial doses of,for example, ginkgo biloba, and separate capsules containing doses orpartial doses of the antioxidant (b) (e.g., apocynin). The pack may beprovided with instructions for sequential administration of the doses.

When administered either together or separately, the compounds (a) and(b) should be such as to maintain a suitable blood level of each of (a)and (b). When administered separately, the compounds (a) and (b) shouldbe given within four hours of each other, preferably within two hours,and more preferably simultaneously.

Preferably, the inflammatory disease is inflammatory respiratorydisease, for example, asthma. The disease may be allergenic in nature.

It is preferred that the preparation is administered orally, forexample, in pill or capsule form, although it is possible to use otherknown conventional administration techniques.

The compositions (and preparations) of the invention may be used as asole treatment. They may also be used alongside conventional medicines(e.g., anti-allergics such as steroids and antihistamines which haveunwanted side affects); this may lead to a reduction in the dose ofconventional medicine required and thus a reduction inlikelihood/occurrence of the side effects. A reduction of side effectsof a therapeutic agent (for example, the side effects of anti-allergicagents) during treatment of human or animal patients being treated isknown as “dose sparing”.

Thus, according to the invention in a still further aspect, there isprovided a method of dose sparing a therapeutic agent comprising thestep of administering to the patient a preparation comprising (a) aPlatelet Activating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade. Preferably, the PlateletActivating Factor (PAF) Inhibitor is ginkgo biloba. Preferably, theantioxidant (b) is apocynin. The preparation may be administered at thesame time as the therapeutic agent (for example, the anti-allergicagent) or at a different time, by the same administration route, or by adifferent administration route.

The examples and description relate (in places) to asthma but it will beunderstood that the preparations of the invention are suitable fortreatment or amelioration or prevention of other diseases, especiallyother inflammatory diseases, as discussed above. These may be, forexample, other respiratory inflammatory diseases such as emphysema. Itwill also be understood that, amongst other things, the preparations ofthe invention are suitable for treatment or diminution of the symptomsof allergic attacks or allergic reactions such as insect bites orstings. The preparations of the invention are suitable for treatment,amelioration or prevention of inflammatory gastrointestinal tractdisorders. The preparations of the invention are suitable for treatmentor prevention of inflammatory diseases, e.g., inflammatory respiratorydisease in animals, for example, dogs and horses.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention will now be exemplified andillustrated with reference to the attached Figures, in which:

FIG. 1 shows the effect of Extracts 2, 5 and 8 alone or in combinationon maximum platelet aggregation in response to ADP 4×10⁻⁶ M (Example13);

FIG. 2 shows the platelet aggregation response to ADP 4×10⁻⁶ M insamples treated with 1) control; 2) 6 μl extract 2; 3) 6 μl extract 5;and 4) 6 μl extract 8 (Example 13); and

FIG. 3 shows the platelet aggregation response to ADP 4×10⁻⁶M in samplestreated with 1) 3 μl extract 2 and 3 μl extract 5; 2) 3 μl extract 2 and3 μl extract 8; 3) 3 μl extract 5 and 3 μl extract 8; and 4) 2 μlextract 2 and 2 μl extract 5 and 2 μl extract 8 (Example 13).

EXAMPLE PREPARATIONS Example 1

The following reagents were mixed:

apocynin 100 mg picorrhiza kurroa 200 mg lactoferrin 60 mg ginkgobiloba** 150 mg bee pollen 120 mg chlorella pyrenoidosa 250 mgphophatidylcholine (lecithin) 100 mg fucus vesiculosus 20 mg Thelactoferrin, bee pollen, chlorella pyrenoidosa, phosphatidycholine(lecithin) and fucus vesiculosus serve as the vehicle. **The ginkgobiloba used was a concentrated extract equivalent dry leaf (that isconcentrated at a ratio 1:4) and standardizd to ginkgo flavone glyosides~18%. Thus, for the same concentration, 600 mg of “natural” ginkgobiloba would be used.

The mixture was divided and prepared in a form suitable for dosing, forexample, in capsule form for oral dose.

Example 1 A

The following compounds were mixed and used for adults and largerchildren:

apocynin 180 g picrorrhiza kurroa 360 g gingko biloba** 260 g chlorellapyrenoidosa 100 g phosphatidyl choline (leicithin) 100 g **gingkobiloba: concentrated extract equivalent to dry leaf 1:4 standardised togingko flavone glycosides ~24%.425 mg (size 0 capsules) per 16 kg body weight: split approximatelytwice daily ⅖ doses in the a.m. and ⅗ doses in the p.m.

Example 1 B

The following compounds were mixed and used for smaller children:

apocynin 100 g picrorrhiza kurroa 200 g ginkgo biloba** 150 g bee pollen100 g chlorella pyrenoidosa 280 g phosphatidylcholine (lecithin) 150 gfucus vesiculosus 20 g **ginkgo biloba: concentrated extract equivalentdry leaf 1:4 standardized to ginkgo flavone glycosides ~24%.425 mg (size 0 capsules) per 8 kg body weight: split twice daily ⅖ dosesin the a.m. and ⅗ doses in the p.m. For small children, the capsule maybe opened and the contents mixed in fruit yogurt.

Example 2 Preventative Treatment of Childhood Asthma

The subject, now a 10 year old girl, had an initial attack of bronchialasthma at 4 years old. Since then, her condition has been serious enoughto require on numerous occasions immediate hospitalization and/orout-patient emergency care. Following an asthma crisis manifested asprolonged unremitting coughing and respiratory distress over some threedays, which necessitated oxygen therapy, repeated broncho dilationtherapy and corticosteroids, the subject was given a daily regime of apreparation according to Example 1.

The dose used was 425 mg of the mixed composition of Example 1 per 8 kgbody weight (daily dose: 2,125 mg in total) split twice daily with ⅖ ofthe doses in the morning and ⅗ in the afternoon. At the end of 15 daysof treatment, the subject became 80–90% symptom free, with an overallimprovement in general health, activity and general well being. Thesubject no longer needed a daily dose (either single or combination doseof corticosteroids, antihistamines and/or bronchodilators; doses whichhad been necessary for five years prior to treatment). No side effectsor problems were observed or reported.

Exercise induced asthma still occurred. However, this occurredsignificantly less frequently and was very much more manageable,generally with minimum bronchodilator therapy. The need for such therapywas further reduced by breathing exercises.

A similar significant response has been observed in children between theages of 18 months and 15 years, although it is noted that with smallchildren the dose may be administered by breaking open the capsule andmixing the dose in a more palatable medium, such as fruit yogurt orhoney.

There may not always be an immediate clinical benefit but over a periodof between 10 to 20 days, a general increase in health occurs due to thecumulative benefits of stabilization and a return to homeostasis. Aswith all “preventative therapeutic approaches”, there remains theproblem of compliance. If the subject stops taking the preparation, areoccurrence of the clinical problems may occur.

During development of the therapy of Example 2, the synergistic effectof ginkgo biloba and apocynin was noted.

Comparison Example 1

Prior to the mixture of Example 1, the subject had been treated withginkgo biloba alone. There was some improvement of the subject'scondition but other medication was still needed; the frequency of use ofmedication (Ventolin inhaler) was reduced during the ginkgo bilobatherapy from daily to 2/3 times per week.

Comparison Example 2

As discussed above, the mixture of Example 1 gave a 90% improvement insymptoms with the first subject, and tests generally gave an improvementof 85–95%, i.e., the subject was symptom free 85–95% of the time.However, administration of a second mixture omitting the ginkgo bilobashowed an improvement in symptoms reduced to only 60%. Further treatmentwith the Example 1 mixture for 15 days increased the improvement to theremarkable 90% symptom free level.

Example 3 Treatment of Childhood Asthma: Therapeutic Dose

Example 2 provides a preventative or maintenance dose with the aim ofpreventing or reducing the frequency of attacks and, therefore,maintaining a level of health. The preparation is also suitable fortreatment of the subject at a “therapeutic level” to alleviate crisissymptoms (e.g., prolonged unremitting coughing) which, if untreated, maylead to hospitalization. For treatment at a therapeutic level, the dailydose is increased by 3–5 times. That is, the daily dose is raised to1275–2125 mg/kg body weight. In general, after 3 days at the therapeuticlevel, the crisis symptoms will have been alleviated and the subject'sdose may then be reduced to the maintenance dose of Example 2.

Example 4 Adult Treatment of Asthma

An adult male subject reported asthma problems which he had suffered forsome 6 to 7 years, caused by an allergy to a cat. The subject was, priorto treatment according to the invention, prescribed preventil andvanceril. These inhalers have been used daily by the subject for theprevious 6 years (two puffs of each inhaler twice or three times daily).Attempts to reduce the medication were problematic and uncomfortable,leading to symptoms such as sleeplessness and breathlessness.

After administration of the dose and preparation of Example 1 for oneweek, the subject reported feeling “terrific”. The subject also reportedbeing able to reduce the frequency of use of preventil and vanceril(reduced to a frequency of one puff a day) without asthmatic flare-up orother side effects.

Example 5

The subject was a 4 year old boy who had had asthma since the age of 2,with a history of chronic ongoing asthma on his father's side of thefamily. His asthma was easily provoked by respiratory tract infections,but less so by environmental allergens. On occasions acute episodes hadrequired emergency hospitalization and emergency management. Previoustreatments used salbutamol (Ventolin) and inhaled corticosteroids (e.g.:Pulmicort/budesonide) as needed. He was treated with Example 1B for fourmonths. Clinical examinations during subsequent respiratory tractinfections have shown no clinical signs/manifestations of asthma. Sincethe start of the treatment, there has been no need for salbutamol orinhaled corticosteroids to control asthma. Salbutamol has been given, onoccasion, during coughing episodes that occur during the infections, butthis was not to control asthma; it appears that the irritant effect fromthe Salbutamol ‘mist inhalation’ provokes a productive sputum coughwhich resolves the coughing.

Example 6

The subject was a 70 year old man who had long term chronic obstructivepulmonary disease (COPD) exacerbated by occasional asthma. He had atypical pronounced barrel chested appearance and chronic shortness ofbreath coupled with chronic productive coughing. Previous treatment waswith salbutamol (Ventolin) and inhaled corticosteroids (e.g.:Pulmicort/budesonide) as needed. He was treated with the composition ofExample 1A and clinical observations at three weeks after the initialtreatment, and thereafter over a period of 3 months, showed asignificant change in facial coloring (blue to red/pink), and minimalproductive sputum coughing. The patient claims to be ‘feeling’ somewhatimproved and insists on continuing the treatment with the composition ofExample 1A. There has been continued clinical improvement with minimumrespiratory discomfort.

In addition to the chronic obstructive pulmonary disease, the patientsuffers from rheumatoid arthritis and since taking the composition ofExample 1A has observed a significant improvement of this condition. Heis now able to undertake tasks and journeys on foot that have not beenpossible for some years.

Example 7

The subject was a 13 year old boy who had suffered from asthma since theage of 5 with a history of chronic ongoing asthma on his father's sideof the family. Attacks were easily provoked by respiratory tractinfections and by environmental allergens. On one occasion, an acuteongoing episode necessitated emergency hospitalization for 5 days. Hewas treated with salbutamol (Ventolin) and inhaled corticosteroids(e.g.: Pulmicort/budesonide) as needed. He was treated with thecomposition of Example 1B for 6 months starting after hishospitalization. After 14 days treatment, he showed no further clinicalsigns of asthma and his asymptomatic state continued for the 6 monthperiod during which he took the composition. After ceasing to take thecomposition, there was a period of some four weeks beforewheezing/asthma resumed.

Example 8

The subject was an 8 year old boy having asthma which was provoked byintense sport/exercise activity. He was treated with salbutamol(Ventolin) and inhaled corticosteroids (e.g.: Pulmicort/budesonide) asneeded. After a period of hospitalization, he was given the compositionof Example 1B. After 10 days of treatment, he displayed no clinicalsigns of asthma during sporting activities.

Example 9

The subject was a 40 year old woman who had suffered from asthma sincechildhood and was allergic to pollen and animals. Previous treatmentsincluded salbutamol (Ventolin) and inhaled corticosteroids (e.g.:Pulmicort/budesonide). After 28 days of taking the composition ofExample 1, all daily inhaled corticosteroids were ceased (suchmedication having been taken daily for many years) and the patientreported a complete resolution of her asthma.

Example 10

The subject was a 40 year old man who had had asthma symptoms sincechildhood and who was allergic to animals (cats and horses). Hisallergies were exacerbated during summer months indicating a possibleadditional allergy to mixed pollens. He had been treated with Proventiland Vanceril over 6 years (two puffs of each 2 or 3 times per day).After 7 days treatment with the composition of Example 1, his asthmasymptoms had resolved with minimum ‘to be on the safe side’ use ofProventil and Vanceril (1 per day of each). After a further two weekstreatment with the composition, he ceased taking the Proventil andVanceril without return of asthma symptoms.

Example 11

The patient was a long term chronic asthma sufferer who was takingmultiple medications (corticosteroids and bronchodilators). After takingthe composition of Example 1A for about 10 days, he reported that hischest congestion was clearing and that he was breathing moreconfidently. He indicated that he no longer “hesitate(s) to runupstairs”.

Example 12

Two children from the same family, both having long term histories ofchronic respiratory disease with asthma-like symptoms and who did notobtain much benefit from using routine corticosteroids/bronchodilators,have, subsequent to taking the composition of Example 1B, been free ofbronchial complications The girl, aged 8, has been taking 1 capsule inthe morning and 2 capsules in the evening, and the boy, aged 6, has beentaking one capsule in each of the morning and evening. Each child hasalso taken one capsule of dimethyl sulphone per day.

Example 13 In Vitro Studies

Extract Preparation

Extracts of components were prepared by stirring macerated samplesovernight in methanol. The mixtures were centrifuged, the supernatantsdrawn off and dried to remove all traces of the extracting solvent.Resulting solids were re-suspended in normal saline (0.9% w/v NaCl) atsaturated concentrations.

Extract No. Ingredient Solvent 2 Apocynin Methanol 5 Picrorrhiza kurroaMethanol 8 Ginko biloba MethanolMethod

Extracts 2, 5 and 8 were reconstituted in 0.9% saline at saturatedconcentrations.

Citrated whole blood, from healthy volunteers, was spun at 900 rpm for20 minutes to obtain platelet rich plasma (PRP). Born aggregometry wasthen carried out within 1 hour of blood being taken. Extracts 2, 5, and8 were added to 450 μl PRP either singly (6 μl), or in combination withone other extract (3 μl each), or all the extracts in combination (2 μleach). PRP was then stimulated with ADP (Sigma) 4×10⁻⁶ M. 6 μl of salinewas added to PRP for the control. Aggregation was measured in a PAP4Caggregometer (BioData Corp. Horsham USA) over 10 minutes.

The dose of agonist was chosen to give slightly sub-optimal aggregationthus showing the maximum effect of any inhibition. Doses of extractswere chosen to show the effect on platelets when used alone and anyadded and/or synergistic effect of using combinations. All data isrecorded as the maximum aggregation.

Results

The results are shown in the following table (“Table Example 13”) andFIGS. 1 to 3.

In the control treatment ADP 4×10⁻⁶ M produce aggregation of 78.5%(Table 1 and FIG. 1).

Extract 2 (FIG. 1 + 2) aggregation in response to ADP reduced by 32%compared with the control. Extract 5 (FIG. 1 + 2) aggregation wasreduced by 6%. Extract 8 (FIG. 1 + 2) aggregation reduced by 29%.Extracts 2 + 5 (FIG. 1 + 3) reduced ADP induced aggregation by 15%.Extracts 2 + 8 (FIG. 1 + 3) aggregation in response to ADP reduced by31%. Extracts 5 + 8 (FIG. 1 + 3) reduced the response to ADP by 45%.Extracts 2 + 5 + 8 (FIG. 1 + 3) aggregation response to ADP reduced by43%.Discussion

Extracts 2, 5 and 8 all reduced platelet aggregation in response to ADP.The combination of extracts 2+5 and 2+8 also caused a reduction in theADP-induced aggregation. The combination of extracts 5+8 added toplatelets reduced aggregation in response to ADP by 45% and thecombination of extracts 2+5+8 reduced the response by 35%; both of thesewere greater than could be predicted by the additive effect of theextracts alone. Thus, in these combinations {(5+8: Picrorrhiza andGinkgo biloba) and (2+5+8: Apocynin and Picrorrhiza and Ginkgo biloba)}the inhibition caused by the extracts works in a manner that is at leastgreater than the predicted additive effect.

Leukotriene receptor antagonists are currently used and approved in thetreatment of asthma. These compounds affect the signal transmissionbetween platelets and immune cells. The components of the pathwaysassociated with these receptors, e.g., arachidonic acid metabolism andPAF stimulation, all appear to be inhibited by the extracts of theapocynin, Picrorrhiza kurroa and Ginkgo biloba mixture.

The fact that the extracts of each component affect the activation ofplatelets and PMN (data not shown) differentially indicates that theextracts affect distinct elements of a number of different activationpathways. They demonstrate a higher effect on PMN than platelets whichappears to support their primary action as an anti-inflammatory mixturein asthma.

The effects of the extracts on platelet aggregation show a markedinhibition of ADP-induced aggregation. ADP-induced aggregation iscritically dependent on cyclooxygenase enzyme activity, an enzyme classblocked by aspirin and used extensively in blood clot prevention. Theseresults provide strong support for the potential application of themixture in reducing thrombosis and cardiac related problems (for exampleischemia and blood flow problems, arrhythmias induced by experimentalmyocardial ischemia, prevention or reduction of arteriolar spasm andproblems caused by thrombus formation).

The fact that there are significant gastrointestinal problems seen inthe use of aspirin offers the mixture as a potential replacement foraspirin therapy. Furthermore, it has been well documented that aspirincan induce asthma. The compositions of the invention, as well as beinguseful in treatment of asthma, may be used instead of aspirin (or NSAIDsof the aspirin type) in treating conditions such as blood clotting inpatients prone to asthma or similar conditions.

Table Example 13: Raw data showing the % aggregation in response to ADPin the presence of extracts 2, 5 and 8 alone or in combination.

ADP 4 × 10⁻⁶ M Extract % Aggregation control 78.5 2-6 μl 53.5 5-6 μl73.5 8-6 μl 55.5 2-3 μl + 5-3 μl 67 2-3 μl + 8-3 μl 54 8-3 μl + 5-3 μl43 2-2 μl + 5-2 μl + 8-2 μl 44.75

Veterinary Examples Example 14 (Dogs)

Dosage

apocynin: 10 mg—50 mg/15 kg body weight per day

ginkgo biloba: 20 mg—100 mg/15 kg body weight per day

picrorrhiza kurroa: 50 mg—100 mg/15 kg body weight per day

phosphatidyl choline: 100 mg—200 mg/15 kg body weight per day.

The regime involves a loading dose (the high figures: apocynin 50 mg/15kg body weight per day; ginkgo biloba 100 mg/15 kg body weight per day;picrorrhiza kurroa: 100 mg/15 kg body weight per day; and phosphatidylcholine: 200 mg/15 kg body weight per day) and a maintenance dose (thelow figures: apocynin 10 mg/15 kg body weight per day; ginkgo biloba 20mg/15 kg body weight per day; picrorrhiza kurroa: 50 mg/15 kg bodyweight per day; and phosphatidyl choline: 100 mg/15 kg body weight perday).

The loading dose is from three to ten days according to individualperceived clinical need. After the loading dose, the maintenance dosefollows for a minimum (normally) of 30 days continuing as needed. Thedoses are scaled according to individual size/body weight.

The composition may be used to treat osteo-arthritic problems,hip-dysplasia and the mature (older/stiffer) dog. In acute cases,although non-steroidal anti-inflammatories (NSAIDs) are required, theNSAID dose can be routinely reduced to ⅛ the recommended/advisedanti-inflammatory dose to achieve the same clinical pain relief whensupplemented additionally with the compositions embodying the invention.

Example 14A

A Viszla (now 8 years old) with obliterative osteoarthritis (O/A) ofboth hind knee joints and O/A of left elbow joint. Originally (at age 2)was unable to bear weight on its hind limbs and now is clinicallysound/well following treatment with the composition (much improvedwithout need of NSAIDs or other anti-inflammatory medications).

Example 14B

A mixed-race dog with O/A from age of eight. Now clinically sound/wellfollowing treatment with the composition (much improved without need ofNSAIDs or other anti-inflammatory medications).

Example 14C

A Doberman with Hip Dysplasia. Sound (much improved without need ofNSAIDs or other anti-inflammatory medications) when taking theformulations of the invention. Unsound and unable to jump when nottaking the formulations.

Example 14D

Labradors (several) with arthritis: sound when on formulations (muchimproved without need of NSAIDs or other anti-inflammatory medications)of the invention—previously unsound.

Example 14E

Treatment of Leishmaniasis (Canine)

This is a life-threatening problem that plagues the Mediterraneancountries. It is, at best, debilitating and requires ongoing supportivemedication with a poor prognosis. A Great Dane in a skeletal conditionwith multiple lymphadenopathies, pustular oozing lesions all over thebody and 80% hair loss was presented after all conventional treatmentregimes had failed. This condition is typical of the terminal phase ofthis disease. After 10 weeks of treatment with the formulations of theinvention (Example 14), it was not possible to distinguish between thisdog and normal healthy other members of his race, i.e., he wasclinically normal.

Example 15 (Horses)

Dosage Horses (450 kg body weight).

apocynin: 100 mg—500 mg per day

ginkgo biloba: 2,000 mg—10,000 mg per day

picrorrhiza kurroa: 500 mg—2,500 mg per day

phosphatidyl choline: 2,000 mg—10,000 mg per day

The regime involves a loading dose (the high figures: apocynin 100 mgper day; ginkgo biloba 2000 mg per day; picrorrhiza kurroa: 500 mg perday; and phosphatidyl choline: 2000 mg per day) and a maintenance dose(the low figures: apocynin 500 mg per day; ginkgo biloba 10000 mg perday; picrorrhiza kurroa: 2500 mg per day; and phosphatidyl choline:10000 mg per day).

The loading dose is from three to ten days according to individualperceived clinical need. After the loading dose, the maintenance dosefollows for a minimum (normally) of 30 days continuing as needed. Thedoses are scaled according to individual size/body weight. The dose wasadded as a powder in the animals' feed.

The compositions used in the following Examples are:

JMJ (Apocynin Mixture)

400 kg of JMJ mix comprising Apocynin (acetovanillone) 0.188 kg and 9.2kg Picrorrhiza kurroa root.

FRS (ginkgo biloba Mix)

103 kg of FRS includes 5 kg ginkgo biloba.

D-Tox

Includes 1 g ginkgo biloba per 15.05 g D-Tox.

JMJ, FRA and D-Tox are available from Nutrilabs of Penrhos, Raglan,Monmouthshire. They are used to make the following Example compositionsaccording to the invention, which were used in Examples A to AA below.The following gives a daily dose for a 450 kg horse. With any of thefollowing Example Compositions during ANY acute phase, a loading dose of3 times the daily dose may be used to assist a rapid return to ‘wellbeing’.

Example PR

dimethyl sulphone (MSM) 2 mg FRS 10 mg JMJ 10 g apocynin 75 mg ferulicacid 100 mg picrorrhiza kurroa 100 mg pancreas extract 100 mg

Example MG

Same as the EXAMPLE PR but includes a medicated shampoo and anMSM/Zinc-based cream for local application.

Example LA

Dimethyl sulphone (MSM) 2 g FRS 15 g JMJ 10 g Apocynin 200 mgpicrorrhiza kurroa 250 mg Chitin/Chitosan 1 g Salvia militorrhiza 2 gThrive 6 gThe above gives a daily dose for a 450 kg horse.

Example RE

dimethyl sulphone (MSM) 3 g FRS 10 g JMJ 10 g apocynin 200 mgpicrorrhiza kurroa 250 mg

Example SU

MSM 2 g FRS 10 g JMJ 15 g glucosamine 500 mg apocynin 200 mg chitin 2 g

Example D-Ty

Viburnum opulus (bark) 2 g FRS Mix 10 g JMJ 10 g ferulic acid 200 mgcimicifuga racemosa 1 g Bynatone (11)# 5 g

Example PF

Dimethyl sulphone (MSM) 2 g FRS 15 g JMJ 10 g Apocynin 200 mgpicrorrhiza kurroa 250 mg Chitin/Chitosan 1 g Salvia militorrhiza 2 gThrive (RTM) 6 g

Example DE

dimethyl sulphone (MSM) 2 g equisetum arvense 2 g FRS 10 g JMJ 15 gurtica dioica 2 g angelica sinensis 1 g liver extract 100 mg salviamiltiorrhiza 1 g rehmannia glutinosa 1 g

The following compositions and methods are within the scope of theinvention.

A. The horse is a 13 year old Welsh Section B mare that had sufferedfrom Seasonal Pruritic Dermatitis since she was two years old. If leftuntreated, she would rub herself raw. Veterinary advice was sought andbenzyl benzoate and stabling were advised. EXAMPLE PR was tried and animprovement was seen within three weeks. The mare now only rubs on veryhot days and benzyl benzoate is only used on a very limited basis. Themare is now shown to be at a very high level of health.

B. The horse is a three-year-old Welsh Cob. Seasonal Pruritic Dermatitiswas seen; veterinary advice was sought and benzyl benzoate wasprescribed. EXAMPLE PR was tried and after five days the horse was doingvery well and continues on a low maintenance level of EXAMPLE PR. Theanimal has been turned out over the summer for the first time in twoyears, with the only other product used being a fly repellent.

C. The horse is a 16.2 h.h, 14 year old mare that has suffered withSeasonal Pruritic Dermatitis on her stomach only during summer monthssince four years of age. She was also aggressive when that area wastouched, e.g.: when the leg was applied. Veterinary advice was soughtand many different approaches were tried but none worked. EXAMPLE PR wastried as a last resort and an improvement was seen within one tub. Themare now only rubs her stomach occasionally and seems much more content.She is easier and happier to ride.

D. The horse, aged 22, had suffered from Seasonal Pruritic Dermatitisfor many years. Veterinary advice was sought and stabling, benzylbenzoate, garlic and antihistamine injections were advised. On advice,EXAMPLE PR was tried. An improvement was seen within one month and hairregrowth was seen within six weeks, while antihistamine treatments wereno longer needed. The horse still rubs occasionally but has a main wherepreviously it was bare, and the tail is no longer rubbed.

E. Housed at the same stable as horse D above, and aged 5, had sufferedfrom Seasonal Pruritic Dermatitis for many years. EXAMPLE PR was tried.An improvement was seen within one month and hair regrowth was seenwithin six weeks. Antihistamines are no longer needed.

F. The horse had suffered from bad Eczematous Dermatitis and filled legswhen stabled every year for the past six years. Veterinary advice wassought and a variety of treatments were tried. The results varied fromimproving the symptoms (Peridine shampoo) to worsening the condition(liquid paraffin). On advice, EXAMPLE MG was tried and an improvementseen within one week. There was an 80% improvement in the filled legs,and no Eczematous Dermatitis occurred at all, all winter.

G. The horse is a 13.2 h.h 10 year old New Forest mare that had sufferedfrom laminitis for four years. Veterinary advice had been sought. X-raysconfirmed the condition and heartbar shoes, increased roughage in thediet, and restricted grazing were advised with only limited results.EXAMPLE L was used and an improvement was seen within two weeks. Thepony is now fit and well and laminitis is not seem with EXAMPLE L beingused as part of an overall management approach.

H. The horse is a 13.2 h.h, 12 year old mare who had previously sufferedfrom laminitis when in foal. She was overweight when put in foal againand the laminitis recurred. Following unsuccessful treatments, it wasdecided to try EXAMPLE L; an improvement was seen within two days ofcommencement of treatment. Within six weeks, there was no sign oflaminitis in the hoof.

I. The horse is a 14 year old Arabian mare which suffered with chronicCOPD for many years. Veterinary advice was sought and Ventipulmin andsteroids were tried. The mare deteriorated to the point where shecouldn't even walk to her field. EXAMPLE RE was tried and an improvementwas seen within one day. The horse is now a happy, fit animal.

J. EXAMPLE SU treatment of a hock deformity in a mare (which had causedlameness and impaired action) gave an “incredible difference” in actionand soundness. Following a dressage competition, localized swelling,heat and intermittent lameness were seen in the near fore. Veterinaryadvice was sought. A mild strain to the check ligament was diagnosed;the horse was given a cortisone injection into the leg and box rest withcontrolled exercise was advised. As the mare was already on EXAMPLE SU,it was suggested that she try D-Tox as well (i.e., treatment continuedwith the effective concentration of ginkgo biloba increased). Three daysafter starting the D-Tox course, the swelling and heat had bothnoticeably reduced. Eleven days after starting, the leg had gone rightdown and all the heat had gone from it. The mare was still on box restbut was being led out to grave for up to 1½ hours daily. Overall themare received a month's course of D-Tox. Two days after finishing theD-Tox, a flare-up of slight swelling and heat was seen again; however,this disappeared over the following two days with careful management.The mare continued on EXAMPLE SU throughout the whole treatment.

Thus, EXAMPLE SU plus D-Tox is within the scope of the invention;increase of concentration of ginkgo biloba may be used to manage chronicsymptoms.

K. Following a number of traumas (a bad fall on the road and severeattack of colic), this horse developed COPD (chronic obstructivepulmonary disease) and a mite allergy at about the same time. Thedevelopment of the problems also coincided with losing summer grazingand having to rely on 1 acre of poor grazing. The neighbor to the fieldcontinually has a dung heap burning (365 days a year), the prevailingwind is over the field and the owner considers that this must contributeto the respiratory condition. The COPD made it impossible to continue incompetition and exercise. Horse K also suffered from an allergicreaction to mites in his fetlocks and heels which caused weeping,bleeding, pus and scabs. This is contributing to his reluctance to work.Ventipulmin (clenbuterol) and Dermobion (nitrofuazone, prednisolone,neomycin, chlorophyll, cod-liver oil) were prescribed by the attendingveterinary surgeon. Ventipulmin had no effect. Dermobion only worked inthe short term. The owner reported that EXAMPLE RE had a “more lastingbeneficial effect”. D-Tox was added and the owner reported a furtherimprovement within three weeks, with full cure of the cough. Slightrespiratory sounds are still heard during fast work, but prior totreatment he was previously unable to do fast work at all; these soundsmay be due to permanent lung damage as this is a long standing condition(˜5 years). Horse K can now go for two-hour hacks without any problem.

L. Having had the mare L for 15 years, the owner had no previousproblems with either weight or laminitis. The vet diagnosed laminitisand prescribed Finadyne injections, followed by powder, remedial shoeingand Bute. A blood test revealed a hormonal imbalance. The mare had beenon Bute for two months but reacted to it, with ulcers around the mouthand sores on the muzzle. The owner was recommended to try D-Tox andEXAMPLE LA. An improvement was seen within a week. The horse is now 95%sound.

M. Despite a careful management regime, the horse suffered from an acuteonset of very severe laminitis; he could barely move. Veterinary advicewas sought and Percutol ointment was tried on all eight digital pulses,along with four sachets of Bute a day, and box rest for six weeks. Nogreat improvement was seen and the horse was given just 24 hours, by thevet, to show an improvement before being put down. The owner was advisedto try D-Tox and EXAMPLE LA. Within twenty-four hours of starting theD-Tox, the horse had been reprieved from being put down, and within fourdays he was moving reasonably freely. He has no built up to three hoursgrass per day and continues to improve. On one day, a slight pulse wasfelt, and the horse was kept in with restricted diet and increased D-Tox(i.e., increased ginkgo biloba) and was fine again within twenty-fourhours.

N. The horse is a twelve-year-old Trakehner x Arab mare who has sufferedfrom occasional intermittent bouts of azoturia over the last six years.There seemed no particular reason for the attacks, and they usuallyoccurred just after exercising. Veterinary advice was sought and vitaminE and selenium were suggested; this had no effect. The mare initiallystarted on D-Tox which she was on for eight months before changing toEXAMPLE D-Ty. No incidence of typing up has been seen since the D-Ty wasfirst introduced. The horse is on one scoop (11 g) of D-Ty together withsalt and a broad based vitamin and mineral provider.

O. The horse is a twenty five year old Anglo Arab who has suffered withEczematous Dermatitis continually for the past five years. Veterinaryadvice was sought and white lead lotion was advised. The owner decidedto try EXAMPLE MG and NAF Teatree Oil Shampoo. Within three weeks, theswelling had reduced, the scabs were softening and falling off, and theskin started to heal very quickly. Within one month, the condition hadhealed completely for the first time in five years.

P. The horse is a 14.2 h.h. 12 year old cob that has suffered fromSeasonal Pruritic Dermatitis (Sweet Itch) for a considerable time.Veterinary advice had been sought and “various lotions and potions” hadbeen prescribed; none had had any significant effect. The owner decidedto try EXAMPLE PR and saw an improvement within two weeks. There isstill a little scratching, but not as severe. There is no inflammationor bald patches and he isn't forever against a tree or fence. The ownerstopped using it for one week and noticed a reversal immediately.

Q. The horse is a 30 year old 13 h.h pony that began to itch. He wouldrub for up to 30 minutes at a time, chew himself until bleeding anddeveloped bald weepy patches. The flanks, chest, rump and shoulders wereaffected, but not the mane or tail, and it continued throughout thewinter so Seasonal Pruritic Dermatitis was ruled out. Veterinary advicewas sought. Skin scrapings were taken, and nothing found. An“unspecified allergy” was diagnosed and medicated shampoo and steroidsprescribed. The horse's owner was keen to avoid steroids and EXAMPLE PRwas used. An improvement was seen in two days, and the owner wascompletely happy with the results within two weeks.

S. The horse is a 5 year old 15.2 h.h gelding who had suffered fromSeasonal Pruritic Dermatitis since he was two and a half. The owner hadtried several different products but none had worked and the horse'sface, mane and tail were rubbed raw. EXAMPLE PR gave an improvementwithin a few weeks. Seasonal Pruritic Dermatitis is now well controlledwhen the animal is fed from April to late September.

T. The horse is a 16 h.h 12 year old Anglo Arab who suffered fromSeasonal Pruritic Dermatitis and raised insect bites, first seen in thesummer of 1999. EXAMPLE PR gave an improvement within four weeks ofcommencement, and the owner was completely happy with the results withinsix weeks. Any obvious insect bites now quickly disappear.

U. The horse is a 19 year old 12 h.h. Welsh Section A gelding. SeasonalPruritic Dermatitis has developed since the age of 12, although mildlyat first he now rubs mane, tail, rump and neck until raw. EXAMPLE PRgave a 90% improvement. The owner thinks that it has been even moresuccessful when used as a preventative. With careful management, thehorse now has a superb coat.

V. The horse is a 14 year old Irish Sport Horse who had always sufferedfrom Eczematous Dermatitis, seen particularly as scabs on his fetlocksand swelling in his white legs. The owner tried EXAMPLE DE and noticedan immediate reduction in the swelling. Fuderex Cream was also usedtopically once the scabs had been removed; it was observed that thescabs did not reappear. The owner continued to use EXAMPLE DE andFuderex Cream as a preventative measure throughout the risk period, andthe horse remained well and unaffected.

W. The horse is an 11 year old Clysdale gelding who suffered withEczematous Dermatitis every year. Veterinary advice had been sought andvarious injections, antibiotics, washes and creams were tried withlittle or no success. EXAMPLE DE gave an improvement within two weeks,despite the challenge being particularly great as the horse hasunclipped, traditional, heavy horse feathers.

X. The animal is a 10 hh 10 year old donkey that had suffered with rainscald annually. Veterinary advice was sought and treating topically withHibiscrub was prescribed. A course of antibiotics was used when theproblem worsened. The owner was advised to try EXAMPLE DE to prevent theproblem from reoccurring. It was obvious that the challenge was stillpresent as slight scabbiness was seen in the early stages, but not asbad as previous years and it quickly cleared completely.

Y. The horse is a ten-year-old miniature Shetland who first sufferedfrom a bout of laminitis in 1997. He remained clear of further attackuntil attending a show in May 1998 where he managed to graze on somerich grass. From that time onwards, the horse's owner described him asalways being “just on the edge.” Veterinary advice was sought from anequine specialist who took X-rays and said that the damage was not toogreat. Electrolytes were prescribed, however they had no effect and noimprovement was seen. Treatment with EXAMPLE PF was so effective thatthe owner was “amazed by the improvement”. Within one month of startingon EXAMPLE PF, the horse was better than he had been for a long time,even giving Bucking Bronco displays for the first time in years just forfun!

Z. The horse is a twenty-year-old pony that suffered his first attack oflaminitis in June 2000. Veterinary advice was sought and he was givenanti-inflammatory and pain killing injections, paste and a month'scourse of powder. An improvement was seen with EXAMPLE PF and the ownerdeclared herself completely satisfied with the product's performancewithin one month. The horse is now well and walks out soundly, neitherthe foot nor sole are sore.

AA. The horse is a 3 year old Shetland gelding that suffers very badlywith skin problems. In addition to Seasonal Pruritic Dermatitis duringthe spring and summer, he also suffers with hives, scabs, sores and poorcoat condition year round. Veterinary advice was sought and dermatitisdiagnosed. Dermobion and insecticidal shampoos were prescribed but noimprovement was seen. The owner had also tried many of the othershampoos, washes, creams and supplements available but not had anyeffect. An improvement was seen within three weeks of starting EXAMPLEPR. The horse now has a clean coat, a 15 cm long mane and a whole tail.The coat is shiny, and the mane silkier. The horse is no longerscratching and his temperament has also improved, presumably due to himno longer being irritated.

Example 16 Example RE Plus

For treatment of horses at 450 kg body weight 20 grams per day. Aloading dose for a period of up to ten days of 100 g/d may be required.

Each 20.2 g of Example RE includes:

MSM (dimethyl sulfone) 3 g Acetovanillone (apocynin) 1 g Phosphatidylcholine (lecithin) 0.5 g Ginkgo biloba (leaf) 2 g Ginkgo biloba(standardised extract: 22% ginkgo flavone glycosides) 0.1 g Picrorrhizakurroa 1 g the balance being herbal extracts and vitamins.

It will be appreciated that other compositions are within the scope ofthe invention.

1. A pharmaceutical composition comprising a unitary dose of ginkgo biloba equivalent to between 1 mg/kg bodyweight and 25 mg/kg body weight ginkgo biloba, standardized to 24% ginkgo flavone glycosides, and a unitary dose of apocynin of between 60 μg/kg body weight and 20 mg/kg body weight.
 2. A composition including apocynin, picrorrhiza kurroa, standardized to a minimum of 2% Kutkin; lactoferrin; ginkgo biloba, standardized to 18% ginkgo flavone glycosides; bee pollen; chlorella pyrenoidosa; phosphatidylcholine; and fucus vesiculosus in the parts by weight ratio of 100:200:60:150:120:250:100:20.
 3. A composition including apocynin, picrorrhiza kurroa, standardized to a minimum of 2% Kutkin; ginkgo biloba, standardized to 24% ginkgo flavone glycosides; chlorella pyrenoidosa; and phosphatidylcholine in the parts by weight ratio of 180:360:260:100:100.
 4. A composition including apocynin, picrorrhiza kurroa, standardized to a minimum of 2% Kutkin; lactoferrin; ginkgo biloba, standardized to 24% ginkgo flavone glycosides; bee pollen; chlorella pyrenoidosa; phosphatidylcholine; and fucus vesiculosus in the parts by weight ratio of 100:200:150:100:280:150:20.
 5. A method of treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting, in a human or non-human animal subject, which comprises the step of administering to the subject the pharmaceutical composition of claim
 1. 6. A method of treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting, in a human or non-human animal subject, which comprises the step of administering to the subject the pharmaceutical composition of claim
 2. 7. A method of treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting, in a human or non-human animal subject, which comprises the step of administering to the subject the pharmaceutical composition of claim
 3. 8. A method of treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting, in a human or non-human animal subject, which comprises the step of administering to the subject the pharmaceutical composition of claim
 4. 9. A method of treating or preventing an inflammatory disease in a human or a non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 1. 10. A method of treating or preventing an inflammatory disease in a human or a non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 2. 11. A method of treating or preventing an inflammatory disease in a human or a non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 3. 12. A method of treating or preventing an inflammatory disease in a human or a non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 4. 13. A kit containing a preparation for treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting in a human or non-human animal subject, comprising at least one dose of the pharmaceutical composition of claim
 1. 14. A kit containing a preparation for treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting in a human or non-human animal subject, comprising at least one dose of the pharmaceutical composition of claim
 2. 15. A kit containing a preparation for treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting in a human or non-human animal subject, comprising at least one dose of the pharmaceutical composition of claim
 3. 16. A kit containing a preparation for treating or preventing an inflammatory disease, thrombosis, cardiac problems and/or conditions caused by platelet induced blood clotting in a human or non-human animal subject, comprising at least one dose of the pharmaceutical composition of claim
 4. 17. A method of dose sparing a therapeutic agent in a human or non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 1. 18. A method of dose sparing a therapeutic agent in a human or non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 2. 19. A method of dose sparing a therapeutic agent in a human or non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 3. 20. A method of dose sparing a therapeutic agent in a human or non-human animal subject comprising the step of administering to the subject the pharmaceutical composition of claim
 4. 